Interactions between glioma and pregnancy: insight from a 52-case ...

CLINICAL ARTICLE

Interactions between glioma and pregnancy: insight from a 52-case multicenter series *Sophie Peeters, BA,1,2 Mélanie Pagès, MD,2,3 Guillaume Gauchotte, MD, PhD,4 Catherine Miquel, MD, PhD,5 Stéphanie Cartalat-Carel, MD,6 Jean-Sébastien Guillamo, MD, PhD,7 Laurent Capelle, MD,8,25 Jean-Yves Delattre, MD, PhD,9 Patrick Beauchesne, MD, PhD,10 Marc Debouverie, MD, PhD,7 Denys Fontaine, MD, PhD,11,25 Emmanuel Jouanneau, MD, PhD,12 Jean Stecken, MD,13 Philippe Menei, MD, PhD,14 Olivier De Witte, MD, PhD,15 Philippe Colin, MD,16,25 Didier Frappaz, MD,17 Thierry Lesimple, MD,18 Luc Bauchet, MD, PhD,19,25 Manuel Lopes, MD,20 Laurence Bozec, MD,21 Elisabeth Moyal, MD, PhD,22 Christophe Deroulers, PhD,23 Pascale Varlet, MD, PhD,2,3,26 Marc Zanello, MD, MSc,1,2 Fabrice Chretien, MD, PhD,2,3 Catherine Oppenheim, MD, PhD,2,24,26 Hugues Duffau, MD, PhD,19,25 Luc Taillandier, MD, PhD,7,25 and Johan Pallud, MD, PhD,1,2,25,26 for the Club de Neuro-Oncologie de la Société Française de Neurochirurgie and the Association des Neuro-Oncologues d’Expression Française Department of Neurosurgery, Sainte-Anne Hospital, Paris; 2Paris Descartes University, Sorbonne Paris Cité, Paris; 3Department of Neuropathology, Sainte-Anne Hospital, Paris; 4Department of Pathology, CHU Nancy; 5Department of Pathology, Saint-Louis Hospital, Paris; 6Department of Neuro-oncology, Hospices Civils de Lyon, Hôpital Neurologique, Bron; 7Department of Neurology, CHU Caen; 8Department of Neurosurgery, Pitié-Salpêtrière University Hospital, Assistance Publique—Hôpitaux de Paris; 9 Department of Neuro-oncology, Pitié-Salpêtrière University Hospital, Assistance Publique—Hôpitaux de Paris; 10Department of Neuro-oncology, CHU de Nancy, Hospital Central, Nancy; 11Department of Neurosurgery, Centre Hospitalier Universitaire de Nice; 12Department of Neurosurgery, Neurological Hospital Pierre Wertheimer, Hospices Civils de Lyon, Bron; 13Department of Neurosurgery, Regional Hospital, Orléans; 14Department of Neurosurgery, CHU d’Angers, France; 15Laboratory of Experimental Neurosurgery and Multidisciplinary Research Institute, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire—Université Libre de Bruxelles, Belgium; 16Department of Radiation, Polyclinique Courlancy, Reims; 17Department of Pediatric and Adult Neuro Oncology, Centre Léon Bérard et Institut Hematology Oncology Pediatric, Lyon; 18Comprehensive Cancer Center and Biotrial, Rennes; 19Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier; 20Department of Neurosurgery, Argonay Private Hospital, Argonay; 21Department of Medical Oncology, Institut Curie-Hôpital René Huguenin, Saint-Cloud; 22Institut Claudius Regaud, Département de Radiothérapie, Toulouse; 23Université Paris Diderot, IMNC Laboratory, CNRS, Université Paris-Sud, Orsay; 24Department of Neuroradiology, Sainte-Anne Hospital, Paris; 25Réseau d’Etude des Gliomes, REG, Groland; and 26Inserm, U894, Centre de Psychiatrie et Neurosciences, Paris, France 1

OBJECTIVE The goal of this study was to provide insight into the influence of gliomas on gestational outcomes, the impact of pregnancy on gliomas, and the identification of patients at risk. METHODS In this multiinstitutional retrospective study, the authors identified 52 pregnancies in 50 women diagnosed with a glioma. RESULTS For gliomas known prior to pregnancy (n = 24), we found the following: 1) An increase in the quantified imaging growth rates occurred during pregnancy in 87% of cases. 2) Clinical deterioration occurred in 38% of cases, with seizures alone resolving after delivery in 57.2% of cases. 3) Oncological treatments were immediately performed after delivery in 25% of cases. For gliomas diagnosed during pregnancy (n = 28), we demonstrated the following: 1) The tumor was discovered during the second and third trimesters in 29% and 54% of cases, respectively, with seizures being the presenting symptom in 68% of cases. 2) The quantified imaging growth rates did not significantly decrease after delivery

ABBREVIATIONS IGF-1 = insulin-like growth factor–1; VDE = velocity of diametric expansion. SUBMITTED March 19, 2016. ACCEPTED October 6, 2016. INCLUDE WHEN CITING Published online March 3, 2017; DOI: 10.3171/2016.10.JNS16710. * Drs. Pagès, Gauchotte, and Miquel contributed equally to this work; and Drs. Taillandier and Pallud contributed equally to this work. ©AANS, 2017

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and before oncological treatment. 3) Clinical deterioration resolved after delivery in 21.4% of cases. 4) Oncological treatments were immediately performed after delivery in 70% of cases. Gliomas with a high grade of malignancy, negative immunoexpression of alpha-internexin, or positive immunoexpression for p53 were more likely to be associated with tumor progression during pregnancy. Deliveries were all uneventful (cesarean section in 54.5% of cases and vaginal delivery in 45.5%), and the infants were developmentally normal. CONCLUSIONS When a woman harboring a glioma envisions a pregnancy, or when a glioma is discovered in a pregnant patient, the authors suggest informing her and her partner that pregnancy may impact the evolution of the glioma clinically and radiologically. They strongly advise a multidisciplinary approach to management. ■ CLASSIFICATION OF EVIDENCE Type of question: association; study design: case series; evidence: Class IV. https://thejns.org/doi/abs/10.3171/2016.10.JNS16710

KEY WORDS glioma management; natural history; oncology; pregnancy

R

improvements in the management of infiltrative cerebral gliomas (WHO Grades II, III, and IV), particularly in young patients with low-grade and IDH-mutated and 1p19q co-deleted gliomas, have resulted in overall better survival and better quality of life.2,3, 7,8,22,23,39,42 As a result, the sustained long periods of disease control and the more favorable prognosis in young and female patients23,24 have led to an increase in the number of women considering pregnancy despite their diagnosis of a glioma.26,41 Moreover, cerebral gliomas can be revealed during a pregnancy even though gravidity does not appear to directly influence a woman’s risk of developing a glioma.42 Gliomas in pregnant patients impose a double risk to both the fetus and the mother. Theoretically, the pregnant patient should receive a treatment similar to a nonpregnant woman, without additional risk to the fetus. However, possible interactions between infiltrative gliomas and pregnancy have not been carefully examined.42 Previous studies have already shown certain trends and correlations of glioma characteristics in the context of pregnancy. These include increased seizure frequency, increased tumor volume and growth rates, and transformation of histopathological grade.6,25 A previous study of 12 WHO Grade II gliomas showed that pregnancy increased seizure frequency, increased glioma growth as observed on images, and further oncological treatment performed immediately after delivery in 40%, 75%, and 25% of cases, respectively.26 A recent study of 18 WHO Grade II and III gliomas has shown that tumor progression occurs during or immediately after pregnancy in 44% of cases.41 A recent study of 53 WHO Grade II gliomas has shown that pregnancy does not seem to impact the survival of patients.32 This multiinstitutional retrospective case series aims to provide additional insight into 1) the influence of gliomas on pregnancy and gestational outcomes, 2) the impact of pregnancy on the evolution of gliomas, and 3) the identification of patients at risk for worsened glioma evolution during and after pregnancy. The practical goal is to better counsel patients in this situation and guide their decision of whether to become pregnant, in the case of a known glioma, or whether to carry a pregnancy to term, in the case of a glioma revealed during gravidity. ecent

Methods

Data Source The French Glioma Study Group together with the 2


French Neurosurgical Society and the Association of French-Speaking Neuro-Oncologists conducted a multiinstitutional retrospective search on adult females treated for primary brain tumors from the French Glioma Study Group and other local institution databases. Criteria for inclusion were: 1) patients older than 18 years at histopathological diagnosis; 2) histopathological diagnosis of WHO Grade II, III, or IV glioma;19 3) supratentorial hemispheric location; 4) a pregnancy at some point during the course of a glioma diagnosis or glioma discovery during pregnancy; and 5) available clinical, obstetrical, imaging, therapeutic, and follow-up data. The institutional review board of the Nancy University Hospital Center approved the study protocol. Data Collection The collected data included patient demographics and pregnancy data (age at glioma diagnosis and at pregnancy, gestational age and trimester at tumor diagnosis, number of abortions and reason, gestational age at birth, and delivery method), clinical characteristics (symptoms at diagnosis, pregnancy outcome, child outcome, clinical course during pregnancy and after delivery, tumor progression, and follow-up), glioma characteristics (WHO histopathological subtype and grade, immunohistochemistry for IDH1 R132H, alpha-internexin, ATRX, p53, Ki 67, estrogen receptors, progesterone receptors, growth hormone receptors, insulin-like growth factor–1 [IGF-1] receptors, histone H3.3 K27 M mutation, histone H3K27 trimethylation, and 1p19q co-deletion status), imaging characteristics (location, volume, contrast enhancement, and imaging growth rates quantified by the velocity of diametric expansion [VDE] using a previously described method;27 see Supplementary Material), and oncological treatments prior to, during, and after pregnancy. Statistical Analyses Results are expressed as the mean ± SD for continuous variables and as percentages for categorical variables. Univariate analyses were carried out using the chi-square test or Fisher’s exact test for comparing categorical variables, and the unpaired t-test or Mann-Whitney rank-sum test for continuous variables, as appropriate. The nonparametric Wilcoxon signed-rank test and the paired t-test were performed, as appropriate, to compare individuals before, during, and after pregnancy. Unadjusted survival

Glioma and pregnancy interactions

■ CLASSIFICATION OF EVIDENCE Type of Question Association Study Design Case Series Evidence Class IV In their paper, Peeters and colleagues summarize the results of their 50-patient case series (representing 52 pregnancies) collected from 2 dozen institutions during an unspecified time period. Twenty-four pregnancies occurred in women with previously diagnosed gliomas, and 28 occurred in women whose gliomas were diagnosed during the course of their pregnancies. Aside from 2 elective abortions (one for oncological and the other for obstetric reasons), all deliveries were uncomplicated, the mix of operative and vaginal deliveries was similar to that in the nontumor population, and both maternal and infant outcomes (at relatively short follow-up) did not appear to be different from those of nonpregnant women with tumors of similar histology and infants of mothers without brain tumors. The authors also suggest that, for the group of patients whose tumors were diagnosed prior to pregnancy, pregnancy accelerated the growth rate of those tumors (velocity of diametric expansion [VDE] of 9.7 ± 14.5 mm/yr vs 1.0 ± 3.2 mm/yr, p < 0.001) and that tumor growth rate fell significantly postpartum (to 2.0 ± 4.9 mm/yr, p = 0.032). This comparison highlights the substantial risk of bias to which all conclusions from case series are subject. Although the patients in this comparison serve as their own controls, there are no comparable nonpregnant women with tumors of similar histology whose VDEs over the course of 36 months can be used for comparison. Furthermore, only 63% of patients (15 of 24) whose tumors were diagnosed prior to pregnancy were available for analysis, and the reason for imaging findings in these particular 15 patients might explain the apparent association of pregnancy with change in tumor size. The outcome measure itself (VDE) was probably determined by unblinded investigators. Perhaps most importantly, the decision to

curves for overall survival and survival before progression requiring an oncological treatment were plotted using the Kaplan-Meier method. A p value < 0.05 was considered significant. Analyses were performed using JMP (version 12.0.0, SAS Institute Inc.).

Results

A total of 62 patients were enrolled, 12 of whom (19.4%) were excluded. Six of these 12 patients had been diagnosed with a glioma postpartum, 3 were still pregnant and without available obstetrical or other follow-up data, and 3 were lost to follow-up. In the end, a total of 50 patients were available. Two of the 50 patients were pregnant twice; therefore, a total of 52 pregnancies were evaluated. Twelve (23.1%) of these 52 cases have been previously reported.26 Glioma Evolution for Patients Diagnosed Prior to Pregnancy For 24 (46.2%) of the 52 pregnancies, the glioma was

become pregnant was likely not random. Patients and their physicians may have believed that tumor progression was unlikely (which, if true, would reduce the apparent association between pregnancy and growth rate), or they may have been eager to carry a pregnancy to term before an anticipated imminent tumor progression. In either case, and for all of these reasons, this case series in general conveys a high risk of bias and carries a Class IV designation. Importantly, combining the results of similar trials using meta-analytic techniques will improve the precision of outcome estimates, but it cannot improve the reliability of those estimates. The authors also provide 2 algorithms for managing these 2 groups of patients: women who become pregnant after the diagnosis of a glioma, and those whose gliomas are diagnosed after conception. Although the authors do not highlight this fact, the 2 groups in their study are substantially different in age (mean difference 3.2 years, p = 0.041), histological composition (WHO Grade II tumors 75% vs Grades III and IV tumors 50%, p = 0.065), need for tumor-directed therapy postpartum (25% [diagnosed prior to pregnancy] vs 70%, p = 0.0008), and death during the follow-up period (8.3% [diagnosed prior to pregnancy] vs 25%, p = 0.11, despite a substantial difference in median follow-up of 70 vs 35 months), justifying separate consideration. The algorithms are rational, but they are based on expert opinion, Class IV evidence, and a nonsystematic literature review. Clinicians need guidance on managing patients in the moment. For this reason, the authors deserve congratulations for their hard work and well-reasoned recommendations. However, clinicians also need reliable guidance. Given the rarity of this important condition, the authors’ most compelling conclusion might be that a high-quality, audited, prospective registry study is desperately needed. — Michael Glantz, MD Hershey Medical Center Hershey, Pennsylvania

discovered prior to the pregnancy. The patients’ main characteristics are summarized in Table 1. Eighteen patients had a WHO Grade II glioma, 4 had a WHO Grade III glioma, and 2 had a WHO Grade IV glioma. The mean age at glioma diagnosis was 26.3 ± 4.9 years, the mean age at pregnancy was 28.6 ± 5.1 years, and the mean time from glioma diagnosis to pregnancy was 28.8 ± 25.4 months. Two patients were pregnant twice after glioma diagnosis (one harboring a WHO Grade II oligodendroglioma and the other harboring a WHO Grade III mixed glioma). All but one of the patients underwent some form of oncological treatment that was achieved at a mean of 17.0 ± 15.3 months before pregnancy. In 5 of these cases, pregnancy began during the 6-month period after oncological treatment; 1 patient underwent radiotherapy (total dose 50.4 Gy) during the first trimester, another received chemotherapy (1 cycle, procarbazine, lomustine, and vincristine) during the first trimester, and the remaining 3 patients underwent resection. While pregnant, 9 patients (37.5%) experienced clinical deterioration (7 with seizures, 1 with a neurological defiJ Neurosurg March 3, 2017

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TABLE 1. Characteristics of 22 patients with a glioma diagnosed prior to pregnancy Variable

Value

No. of pregnancies General findings Median age at glioma diagnosis, yrs WHO glioma grade II III IV Before pregnancy Oncological Tx before pregnancy None Surgery alone Surgery + radiotherapy Surgery + chemotherapy Surgery + radiotherapy + chemotherapy Radiotherapy alone Chemotherapy alone Radiotherapy + chemotherapy Mean interval btwn diagnosis & pregnancy, mos Mean interval btwn oncological Tx & pregnancy, mos During pregnancy Clinical presentation None Epileptic seizures only Neurological deficit Increased intracranial pressure Imaging progression New contrast enhancement Increase in tumor growth on imaging compared w/ prepregnancy status No Yes Missing Oncological Tx None Biopsy Resection Chemotherapy Radiotherapy After pregnancy Oncological Tx None Surgery alone Surgery + radiotherapy + chemotherapy Chemotherapy alone Radiotherapy + chemotherapy Median interval btwn oncological treatment & delivery, mos

24 26.0 (19–37) 18 4 2

1 11 4 1 5 0 1 1 21.3 (3–100) 20.5 (0–58)

15 7 1 1 0

2 13 9 22 0 0 1 1

14 3 2 3 2 4.0 (1–59)

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TABLE 1. Characteristics of 22 patients with a glioma diagnosed prior to pregnancy Variable After pregnancy (continued) Gestational outcomes Median term of delivery, wks Abortion Delivery Cesarean Vaginal Missing Infant outcomes Healthy infant Malformations Developmental delay Missing Patient outcomes Mean duration of follow-up, mos Tumor progression Death

Value

39.0 (35–41) 1 10 8 6 18 0 0 6 69.8 (24–164) 9 2

Tx = treatment. Median values are presented with the ranges in parentheses. The other values represent the number of pregnancies.

cit, and 1 with increased intracranial pressure). No new contrast enhancement or hemorrhage was observed on follow-up MRI during pregnancy. The quantitative imaging follow-up before and during pregnancy was available in 15 cases (14 WHO Grade II gliomas, 1 WHO Grade III; 8 without and 7 with oncological treatment before pregnancy impacting the VDE). Tumor progression, defined by an increase in the VDE, was observed during pregnancy in 13 cases (86.7%), and to levels at least 2 times higher than values before pregnancy in 11 cases (73.3%) (Fig. 1). The increase in VDE during pregnancy (mean 9.7 ± 14.5 mm/yr) compared with prepregnancy values (mean 1.0 ± 3.2 mm/yr) was significant (p < 0.001). The presence of tumor progression on MRI during pregnancy was not correlated with clinical deterioration (p = 0.759). None of these women had an abortion for oncological reasons (one for fetal reasons unrelated to the glioma management), and 5 patients had spontaneous preterm deliveries (mean 35.3 ± 0.5 weeks, range 35–36 weeks) unrelated to the postdelivery oncological management. After delivery, 4 patients with seizures (57.1%) improved, but the neurological deficit and the increased intracranial pressure did not improve. Of the 15 patients with available quantitative imaging studies before and during pregnancy, 9 patients had available follow-up imaging after delivery; 3 of the remaining 6 patients underwent oncological treatment immediately after delivery that impacted the VDE, and MRI data were missing in the remaining 3 cases. In these patients, the VDE decreased after delivery in 7 (77.8%) cases at significant rates (mean 2.0 ± 4.9 mm/ yr) compared with those during pregnancy (p = 0.032) and did not significantly differ from prepregnancy rates


FIG. 1. Effects of pregnancy on glioma growth rates on imaging follow-up. A: Effect of pregnancy on the VDE in the 8 available patients with a glioma diagnosed before pregnancy who did not receive oncological treatment impacting the VDE before pregnancy. Before pregnancy, the mean VDE was 2.6 ± 1.4 mm/yr (range 0.8–4.2 mm/yr). The mean VDE during pregnancy was 13.4 ± 20.2 mm/yr (range 1.8–62.7 mm/yr). The increase in VDE during pregnancy compared with prepregnancy values was statistically significant (p = 0.027). The postdelivery mean VDE was 4.2 ± 5.1 mm/yr (range 0.8–12.8 mm/yr). Velocities of diametric expansion values after delivery were decreased at statistically significant levels compared with those during pregnancy (p = 0.033) but were not significantly different from prepregnancy rates (p = 0.221). B: Examples of the evolution of the glioma mean tumor diameter (mm) over time before (left), during (center), and after (right) pregnancy. Circle case: Evolution of the imaging growth rate of a bifrontal WHO Grade II oligodendroglioma treated by partial surgical removal 14 months before pregnancy. Before pregnancy (left), the tumor grew continuously with a VDE of 1.4 mm/yr. During pregnancy (center), the tumor growth rate increased with a VDE of 11.3 mm/yr without clinical deterioration. After delivery (right), the VDE decreased 1.6 mm/yr without particular oncological treatment. Asterisk case: Evolution of the imaging growth rate of a right frontal WHO Grade II astrocytoma treated by partial surgical removal and chemotherapy (procarbazine, lomustine, and vincristine, 6 cycles) 16 months before pregnancy. Before pregnancy, the tumor volume decreased with time, with a negative VDE at -4.0 mm/yr. During pregnancy, the tumor growth rate increased with a VDE of 8.0 mm/yr. After delivery, the VDE decreased to 3.7 mm/yr but remained higher than the prepregnancy value. C: Effect of pregnancy on the VDE in the 7 available patients with a glioma diagnosed before pregnancy who received an oncological treatment impacting the VDE before pregnancy. Before pregnancy, the mean VDE was -1.8 ± 3.3 mm/yr (range -5.3 to 1.6 mm/yr). The mean VDE during pregnancy was 6.1 ± 3.8 mm/yr (range 1.6–11.7 mm/yr). The increase in VDE during pregnancy compared with prepregnancy values was statistically significant (p = 0.032). The postdelivery mean VDE was -0.1 ± 4.1 mm/yr (range -4.2 to 3.9 mm/yr). Velocities of diametric expansion values after delivery were decreased at statistically significant levels compared with those during pregnancy (p = 0.039) but were not significantly different from prepregnancy rates (p = 0.234). CT = chemotherapy; RT = radiation therapy.

(p = 0.563). Ten patients (42%) required oncological treatment during the follow-up period at a mean of 17.2 ± 23.0 months following delivery. Six patients (25%) received treatment in the 6 months after delivery (mean 2.6 ± 1.5 months, range 1–4 months) due to clinical deterioration in 2 cases, tumor progression on MRI in 2 cases, and clinical deterioration plus tumor progression in 2 cases. Oncological treatment performed during the first 6 months after delivery was associated with clinical deterioration and/or tumor progression on MRI, without reaching significance (p = 0.073). At the end of the follow-up period, 9 (37.5%) patients experienced recurrence, and 2 (8.3%) had died of their disease (2 WHO Grade II gliomas). Glioma Evolution for Patients Diagnosed During Pregnancy In 28 (53.8%) of the 52 pregnancies, the glioma was discovered during the pregnancy. The patients’ main characteristics are summarized in Table 2. The mean age at pregnancy was 29.5 ± 6.1 years. Gliomas were diagnosed during the first, second, and third trimesters of pregnancy

in 17.8%, 28.6%, and 53.6%, respectively. Of these patients, 19 (68%) presented with seizures, 4 (14%) with a neurological deficit, and 5 (18%) with increased intracranial pressure. No hemorrhage was observed on follow-up MRI during pregnancy. Five patients (17.9%) underwent surgery during the pregnancy (1 biopsy, 3 resections, and 1 resection plus radiotherapy). Three of these 5 patients were treated during the third trimester, 1 during the first trimester, and 1 during the second trimester. One of these women who was diagnosed with a glioma during pregnancy terminated her pregnancy for oncological reasons (radiotherapy) during the second trimester. Four patients underwent a planned delivery that was performed during the third trimester (mean 32.7 ± 2.8 weeks, range 29–35 weeks) to allow the oncological treatment at a mean 0.7 ± 0.9 months (range 0–2 months) after delivery. After delivery, clinical deterioration resolved in 6 patients (21.4%; 3 patients with seizures, 2 with increased intracranial pressure, and 1 with neurological deficit) compared with their status during pregnancy. The quantitative imaging follow-up during and after pregnancy before onJ Neurosurg March 3, 2017

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TABLE 2. Characteristics of 28 cases of patients with a glioma diagnosed during pregnancy Variable During pregnancy Median age at glioma diagnosis, yrs WHO glioma grade II III IV During pregnancy Clinical presentation None Epileptic seizures only Epileptic seizures + neurological deficit Neurological deficit Increased intracranial pressure Missing Oncological Tx None Biopsy Resection Chemotherapy Surgery + radiotherapy After pregnancy Oncological Tx None Surgery alone Surgery + radiotherapy Surgery + chemotherapy Surgery + radiotherapy + chemotherapy Radiotherapy alone Chemotherapy alone Radiotherapy + chemotherapy Median interval btwn oncological Tx & delivery, mos Gestational outcomes Median term of delivery, wks Abortion Delivery Cesarean Vaginal Missing Child outcomes Healthy infant Malformations Developmental delay Missing Patient outcomes Mean duration of follow-up, mos Tumor progression Death 6


No. of Pregnancies (n = 28) 29.5 (20–43) 14 10 4

0 17 2 2 5 2 23 1 3 0 1

3 10 3 1 5 1 2 3 2.0 (0–16)

40.5 (29–41) 1 (at 14 wks) 8 8 12 21 0 0 7 34.6 (3–175) 14 7

cological treatment impacting the VDE was available in 4 cases (4 WHO Grade II gliomas). The postpregnancy VDE (mean 10.1 ± 4.7 mm/yr) did not significantly decrease compared with the VDE during pregnancy (mean 23.5 ± 15.1 mm/yr; p = 0.250). Twenty-five patients (89.3%) underwent oncological treatment at a mean of 4.0 ± 4.8 months following delivery. Sixteen patients (69.6%) received prompt treatment in the 6 months after delivery (mean 1.6 ± 1.6 months, range 0–6 months). Of the 3 women who did not receive treatment after delivery, 2 underwent oncological treatment during pregnancy and 1 declined treatment. Fourteen patients had a WHO Grade II glioma, 10 had a WHO Grade III glioma, 3 had a WHO Grade IV glioma, and 1 had a malignant pleomorphic xanthoastrocytoma. At the end of the follow-up period, 14 (50%) patients experienced recurrence and 7 (25%) ultimately died of their disease (5 WHO Grade II gliomas and 2 WHO Grade III gliomas). Gestational Outcomes Of the 52 studied pregnancies, 2 were terminated: 1 for oncological reasons (radiotherapy) at 14 weeks of pregnancy in a woman diagnosed with a glioma during pregnancy, and 1 for fetal reasons unrelated to the glioma management at 20 weeks of pregnancy in a woman diagnosed with a glioma prior to pregnancy. The mean gestational age for the 50 continued pregnancies was 38.4 ± 2.9 weeks. Although there were no postterm deliveries, there were 9 preterm babies (4 planned deliveries in patients with a glioma diagnosed during pregnancy and 5 spontaneous preterm deliveries in patients with a known glioma prior to pregnancy). For women diagnosed with a glioma during pregnancy with available detailed method of delivery information (n = 16), 50% had a cesarean section and 50% delivered vaginally without any adverse events. For women diagnosed with a glioma prior to pregnancy with a detailed method of delivery (n = 18), 55.6% had a cesarean section and 44.4% delivered vaginally without any adverse events. All infants delivered with an available follow-up (n = 39; 39.5 ± 48.3 months) were developmentally normal. Predictors of Glioma Evolution During Pregnancy The increase in the VDE during pregnancy was significantly more frequent in patients who required oncological treatment for tumor progression after delivery (100%) than in those who did not (60%; p = 0.047). Similarly, the VDE decrease following delivery was significantly less frequent in patients who required an oncological treatment for tumor progression after delivery (66.7%) than in those who did not (100%; p = 0.049). Immunoexpression for estrogen and progesterone receptors was assessed in 32 patients with available tissue (20 WHO Grade II, 9 WHO Grade III, and 3 WHO Grade IV). Immunoexpression for growth hormone and IGF-1 receptors was assessed in 28 patients with available tissue (18 WHO Grade II, 7 WHO Grade III, and 3 WHO Grade IV). As detailed in Table 3, no positive immunoexpression was observed for estrogen, progesterone, or growth hormone receptors. A positive immunoexpression for IGF-1 receptor was observed in 57.1%, with the expression rate increasing with WHO grade of malignancy (p =


TABLE 3. Immunoexpression of hormone receptors Receptor Estrogen Progesterone Growth hormone IGF-1 receptor WHO grade II III IV

No. of Patients

No. w/ Positive Immunoexpression (%)

32 32 28 28

0 0 0 16/28 (57.1)

18 7 3

8/18 (44.4) 5/7 (71.4) 3/3 (100)

0.051). For patients in whom a glioma was diagnosed prior to pregnancy, the negative immunoexpression for alphainternexin (43% vs 100%, p = 0.094) and the positive immunoexpression for p53 (100% vs 50%, p = 0.061) tended to be associated with an increase in the VDE during pregnancy at least 2 times higher than prepregnancy rates. Survival Analyses The median patient survival before progression requiring an oncological treatment did not significantly differ between WHO Grade II gliomas discovered during pregnancy (n = 14; 46.0 months) and those discovered prior to pregnancy (n = 18; 55.0 months, p = 0.664). The median survival before progression requiring an oncological treatment did not significantly differ between WHO Grade III gliomas discovered during pregnancy (n = 10; 31.0 months) and those discovered prior to pregnancy (n = 4; not reached, p = 0.185). The median survival before progression requiring an oncological treatment did not significantly differ between WHO Grade IV gliomas discovered during pregnancy (n = 4; 19.0 months) and those discovered prior to pregnancy (n = 2; 36.0 months, p = 0.257). The median overall survival was not reached for patients with a WHO Grade II glioma at a mean follow-up of 57.7 ± 40.0 months, for patients with a WHO Grade III glioma at a mean follow-up of 69.4 ± 52.9 months, and for patients with a WHO Grade IV glioma at a mean followup of 31.3 ± 21.1 months.

Discussion

This multiinstitutional retrospective study has shown that pregnancy impacts the evolution of supratentorial infiltrative gliomas. For gliomas known prior to pregnancy, we demonstrated that: 1) an imaging progression, quantified by an increase in VDE and not systematically associated with a clinical deterioration, occurred during pregnancy in 87%; 2) clinical deterioration occurred in 38%, with only seizures resolving after delivery in 57.2%; and 3) oncological treatments may be needed after delivery in 42% of cases and performed in the 6 months after delivery in 25% due to clinical and/or imaging deterioration. For gliomas diagnosed during pregnancy, we demonstrated that: 1) the tumor is discovered during the second and third trimesters in 29% and 54%, respectively, with seizures being the presenting symptom in 68% of cases; 2) imaging progression,

quantified by an increase in VDE, did not significantly decrease after delivery and before oncological treatment; 3) clinical signs resolved after delivery in 21.4%; and 4) oncological treatments are performed in the 6 months after delivery in 70%. We identified high-risk gliomas (WHO Grade III and IV, negative immunoexpression of alphainternexin, positive immunoexpression for p53) as being associated with tumor progression during pregnancy. Pregnancy Effects on Gliomas The clinical presentation of gliomas during pregnancy appears comparable to the clinical picture outside of gravidity.7,34,37 The facts that gliomas diagnosed during pregnancy are discovered predominantly during the second or third trimester of pregnancy,2,22,38,40,42 that patients with a known glioma prior to pregnancy experience clinical deterioration during pregnancy,6,31,42 and that seizures have previously been shown as a common presenting symptom12,22,25,26,34,37,41,42 suggest an impact of pregnancy-related biological changes on the glioma’s behavior and its epileptogenicity. Beyond seizures, pregnancy has been reported to exacerbate neurological symptoms, which may precipitate obstetrical emergencies.15,25,30,42 In the present series, no neurological or obstetrical emergencies related to the pregnancy were observed. This suggests that conservative management and symptomatic treatment are a reasonable approach in this patient population. In the current study, we observed an imaging progression during pregnancy in about 90% of cases. Contrary to the dogma that pregnancy has not convincingly been shown to accelerate glioma growth,2,7 the present results, using a quantitative approach on imaging, suggest a dismal, though transient, effect, of pregnancy on glioma behavior. These results should be interpreted with caution due to the small sample population, lack of a nonpregnancy female control group, lack of volumetric glioma growth rate analyses after delivery due to oncological treatment performed shortly after delivery in several patients, and absence of systematic contrastenhanced MRI examinations given the contraindication during pregnancy. The clinical deterioration and radiological tumor progression we observed prompted prenatal oncological treatment in 18% of patients with a glioma diagnosed during pregnancy, 70% received treatment shortly after delivery, and 25% of the patients with a glioma known prior to pregnancy received treatment shortly after delivery. Altogether, the present findings clearly suggest a link between pregnancy and glioma growth, thus raising concerns for women with gliomas considering childbearing. Lastly, although no conclusion could be drawn for the present survival analyses, pregnancy does not seem to markedly alter the outcomes of patients harboring a glioma, in accordance with a recent study dedicated to WHO Grade II glioma;32 this could possibly be linked to young age, good overall condition, tumor control at the time of pregnancy, and oncological treatments. Glioma Effects on Gestational Outcomes and Newborns The potential impact of a glioma on gestational outcomes is difficult to assess, as the symptomatic management (antiepileptic drugs) and the oncological treatments may interact synergistically with the glioma during the J Neurosurg March 3, 2017

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FIG. 2. Algorithm for management of supratentorial gliomas known before pregnancy. AED = antiepileptic drug. The asterisks indicate that these options were proposed after discussion and information.

course of the pregnancy and with the in utero development of the child. Preterm deliveries and cesarean deliveries have been reported in pregnant women harboring a glioma,15,25, 30,42 and terminations may be performed to conduct oncological treatment. In the present study, all but 2 patients for whom abortion was performed (one termination for fetal reasons and the other for oncological reasons) had uneventful pregnancies with deliveries at a mean term of 38.4 weeks (9 preterm deliveries). The deliveries, all uneventful and without adverse events, were conducted through a vaginal method or cesarean section in about 45.5% and 54.5% of cases, respectively, without specific reasoning for one mode of delivery over the other. The rate of cesarean sections in those patients was in accordance with previous studies that encourage cesarean sections, predominantly in cases of increased intracranial pressure at the time of delivery.2,22,41,42 In all available cases, albeit with limited followup, the babies were healthy, as previously reported,2,12,22,26 including those whose mothers received radiotherapy and chemotherapy during the first trimester. Possible Mechanisms for the Findings Regarding Tumor Changes With Pregnancy Three main hypotheses have been suggested as respon8


sible for the clinical and radiological worsening observed during pregnancy: immunological tolerance, steroid-mediated glioma growth, and hormone-related effects.1,5–7 The presence of pregnancy-induced hormonal changes may lead to fluid retention, increased vascular volume, and peritumoral edema that may exacerbate an intracranial mass effect.2,7,12,18,26 In addition, progesterone enhances glioma cell growth in humans,10 and expression of progesterone receptors is increased with glioma grade as well as invasion and migration markers.9,15,17 Contrarily, estrogen triggers growth inhibition and apoptosis in glial cells.5,11,16 Secretion of placental growth hormone at the maternalplacental interface stimulates secretion of growth factors, such as insulin-like growth factors, known to play a role in the proliferation and migration of glial cells, as well as secretion of pituitary gonadotropins, which also have receptors on tumor cells.18,42 Insulin-like growth factors–1 and –2 regulate and strongly stimulate glial cell migration and glioma growth.14,33 However, in the present study, no progesterone, estrogen, or growth hormone receptors were identified, as previously reported.29 Only a positive expression of the IGF-1 receptor was identified; the expression rate increased with the WHO grade of malignancy but without clear correlation with glioma evolution during


FIG. 3. Algorithm for management of supratentorial gliomas in pregnant women. The asterisks indicate that these options were proposed after discussion and information.

pregnancy. Thus, although no definite conclusion can be drawn, the present analysis does not support a hormonalrelated effect of pregnancy on glioma growth. Feasibility of Oncological Treatment Peripartum Pregnancy makes oncological guidelines complicated, as not all oncological treatments are approved for use in pregnant women. In addition, management strategies are complicated by a variety of clinical and social factors.2 Consequently, only a tentative practical management plan for pregnant patients harboring a supratentorial infiltrative glioma can be drawn through focusing on a multidisciplinary approach. Based on the results we have obtained and on a synthesis of those in previous reports,2,6,7, 13,21,26,28,35,42 we propose algorithms for the management of the pregnancy in a patient diagnosed with a glioma prior to pregnancy (Fig. 2) and with a glioma discovered during the pregnancy (Fig. 3). A watchful waiting policy can be proposed for women diagnosed with the glioma in their first and early second trimesters if a stable, low-grade glioma is suspected.1,4,12, 13,20,36–38 For women whose condition is stable but who are in their late second or third trimester of pregnancy, gestational advancement to term should be considered. Delivery is an acceptable option prior to oncological treatment

for the women with progressing neurological signs.1,4,7,13 For unstable patients, urgent neurosurgery is the standard of care for first and early second trimester patients. The question of terminating the pregnancy should be considered if the patient’s condition is quickly deteriorating and the gestational age is far from fetal viability. For unstable patients in their late second trimester to term, a cesarean section followed by urgent neurosurgery is recommended, although some studies discuss the possibility of performing a craniotomy prior to the delivery.4,12,20

Conclusions

The present study, through its retrospective design, small sample size, and heterogeneity with regard to glioma subtype and grade, stage of pregnancy, tumor location, and therapeutic management, requires prudence with potential guidelines for pregnancy management in women with a supratentorial glioma. When a woman harboring a glioma envisions a pregnancy, or when a glioma is discovered in a pregnant patient, we suggest counseling her and her partner and informing them of the following: 1) We have very little knowledge of the condition, and no definite guidelines exist. 2) Completion of the pregnancy is feasible with the birth of a healthy baby. 3) The pregnancy may accelerJ Neurosurg March 3, 2017

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S. Peeters et al.

ate glioma growth, may exacerbate clinical deterioration, and may prompt oncological treatments earlier than in the general population with a glioma. 4) No data confirm that pregnancy impacts the survival of a patient harboring a glioma. 5) The potential need for oncological treatment during pregnancy has serious known hazards for the fetus. 6) There are potential problems associated with controlling seizures in addition to the well-documented risks of congenital abnormalities from antiepileptic drug therapy. 7) The timing and choice of obstetrical interventions matter. 8) Some intense oncological treatments may impact the child’s growth and development. 9) In the case of malignant gliomas, life expectancy of the mother is reduced compared with the general population, and the child is at very high risk of losing the mother. In all cases, we strongly advise a multidisciplinary approach to management.26,42 Clinically, we recommend the following: 1) careful and frequent neurological follow-up during pregnancy and after delivery; 2) routine MRI follow-up with quantitative assessment of the glioma during gestation; and 3) rigorous obstetrical monitoring.

Acknowledgments

This study was supported by Contrat de Programme de Recherche Clinique (CPRC) of the Centre Hospitalier Universitaire de Nancy, France. These physicians are greatly acknowledged (in alphabetical order): Georges Abi-Lahoud, Sorin Aldea, Felipe Andreiuolo, Mathilde Badoual, Alexandra Benouaich, Michèle Bernier, Marie Blonski, Fanny Burel-Vandenbos, Valérie Cahn, Charlotte Carnin, Francine Chassoux, Catherine Daumas-Duport, Bernadette Delisle, Stéphane Derrey, Bertrand Devaux, Edouard Dezamis, Frédéric Dhermain, François Ducray, Sarah Dumont, Julien Duntze, Evelyne Emery, Myriam Edjlali-Goujon, Khé Hoang Xuan, Michel Fabbro, Marie Fregeville, Marc Frenay, Henri-Dominique Fournier, Aurore Gendre, Sylvie Godon-Hardy, Anne Heitzmann, Khe Hoang-Xuan, Anne Jouvet, Maria Koziak, Ludovic Lacroix, Elisabeth Landré, Emmanuelle Lechapt-Zalcman, Laurence Legrand, Franck Letournel, Fabien Litré, Hugues Loiseau, Guillaume Louvel, Emmanuel Mandonnet, Michael Mann, Béatrice Marie, Jean-Louis Mas, Eric Méary, Jean-François Meder, Charles Mellerio, Karima Mokhtari, Olivier Naggara, François Nataf, Catherine Oppenheim, Philippe Page, Philippe Peruzzi, Michel Pluot, Valérie Rigau, Alexandre Roux, François-Xavier Roux, Isabelle Salmon, Stephan Saikali, Marc Samson, Xavier Sauvageon, Sylvie Sicot, Etienne Théret, Denis Trystram, Baris Turak, and Jean-Michel Vignaud.

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Disclosures

Dr. Varlet states that he has personal relationships with Novartis, Boehringer, and Roche.

Author Contributions

Conception and design: Pallud, Taillandier. Acquisition of data: Pallud, Pagès, Gauchotte, Miquel, Cartalat-Carel, Guillamo, Capelle, Delattre, Beauchesne, Debouverie, Fontaine, Jouanneau, Stecken, Menei, De Witte, Colin, Frappaz, Lesimple, Bauchet, Lopes, Bozec, Moyal, Deroulers, Varlet, Zanello, Chretien, Oppenheim, Duffau, Taillandier. Analysis and interpretation of data: Pallud, Peeters, Pagès, Gauchotte, Deroulers, Duffau. Drafting the article: Pallud, Peeters. Critically revising the article: Pallud, Peeters, Pagès, Gauchotte, Miquel, Delattre, Beauchesne, Bauchet, Deroulers, Duffau, Taillandier. Reviewed submitted version of manuscript: Pallud, Peeters, Taillandier. Approved the final version of the manuscript on behalf of all authors: Pallud. Statistical analysis: Pallud. Administrative/technical/material support: Pallud, Taillandier. Study supervision: Pallud.

Supplemental Information Online-Only Content

Supplemental material is available with the online version of the article. Supplementary Material. https://thejns.org/doi/suppl/10.3171/ 2016.10.JNS16710.

Correspondence

Johan Pallud, Service de Neurochirurgie, Hôpital Sainte-Anne, 1 rue Cabanis, 75674 Paris Cedex 14, France. email: johanpallud@ hotmail.com.


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